Chemicals signals

Page Last modified 08 Dec 2022
7 min read
This section of the zero pollution monitoring assessment presents a series of short case studies that highlight additional sources of information on the impacts of chemical pollution on health.

Chemicals Signal 1: Regrettable substitution

Regrettable substitution happens when a chemical is used to replace a problematic one — but the substitute chemical also turns out to be hazardous (Maertens et al., 2021). As research reveals new information on the hazards associated with specific chemicals, risk assessment and risk management measures are updated. As a result, chemicals formerly considered safe can later be identified as problematic and, in turn, their use can become regulated.

An example of a chemical previously used in high volumes is the plasticiser bis(2-ethylhexyl) phthalate (DEHP). After DEHP was classified as both an endocrine disruptor and a substance toxic to reproduction, it was regulated under REACH as a substance of very high concern. Authorisation is required to use it, and some uses are restricted (ECHA, 2016) to reduce the risk of human contact. Data from Germany presented in Figure 1 show how population exposure to DEHP declined rapidly from a peak in the early 1990s. It is estimated that exposure levels today are around 95% lower than they were 30 years ago.

However, DEHP regulation did not remove the general need for plasticisers. One of the main substitutes developed to replace DEHP is 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH). As shown in Figure 1, human exposure to DINCH in Germany has steadily increased following its introduction to the market in 2002.

Although DINCH is less toxic than DEHP, it can cause kidney damage. Human exposure to DINCH is currently lower than historical exposure to DEHP. Nevertheless, data on DINCH in German children already show cases of individuals exhibiting levels exceeding the health-based guidance values for DINCH (Schwedler et al., 2020). This poses a potential health risk to a highly exposed population.

Under the chemicals strategy for sustainability, the European Commission proposes a more integrated approach to chemical risk assessment. This especially applies to chemicals with similar hazards, risks or functions. Regulating substances individually is a very time-consuming process and does not effectively or efficiently reduce the risks posed by chemicals.

When substituting hazardous substances, the alternatives should be safe and sustainable by design. DINCH is less toxic than DEHP, but its current use levels are not safe. Shifting to safe and sustainable by design approaches could help avoid regrettable substitution in the future (Caldeira et al., 2022).

Figure 1. Measurements in urine samples from 20- to 29-year-old student volunteers of the German Environmental Specimen Bank

Sources: Koch et al. (2017); Kasper-Sonnenberg et al. (2019).

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Caldeira, C., et al., 2022, Safe and sustainable by design chemicals and materials — framework for the definition of criteria and evaluation procedure for chemicals and materials, Publications Office of the European Union, Luxembourg ( accessed 21 October 2022.

ECHA, 2016, ‘Annex XVII to REACH — conditions of restriction’, European Chemicals Agency ( accessed 18 October 2022.

Kasper-Sonnenberg, M., et al., 2019, ‘Time trend of exposure to the phthalate plasticizer substitute DINCH in Germany from 1999 to 2017: biomonitoring data on young adults from the Environmental Specimen Bank (ESB)’, International Journal of Hygiene and Environmental Health 222(8), pp. 1084-1092 (

Koch, M., et al., 2017, ‘Phthalate metabolites in 24-h urine samples of the German Environmental Specimen Bank (ESB) from 1988 to 2015 and a comparison with US NHANES data from 1999 to 2012’, International Journal of Hygiene and Environmental Health 220(2A), pp. 130-141 (

Maertens, A., et al., 2021, ‘Avoiding regrettable substitutions: green toxicology for sustainable chemistry’, ACS Sustainable Chemistry & Engineering 9(23), pp. 7749-7758 (

Schwedler G., et al., 2020, ‘Hexamoll® DINCH and DPHP metabolites in urine of children and adolescents in Germany. Human biomonitoring results of the German Environmental Survey GerES V, 2014–2017’, International Journal of Hygiene and Environmental Health 229, p. 113397 (

Chemicals Signal 2: How chemical mixtures affect human health

Studies demonstrate that our bodies are polluted with complex chemical mixtures. Combined exposure to multiple chemicals can have health effects, even if single substances in the mixtures meet individual safety thresholds (Kortenkamp, 2008).

A recent study investigated European exposure to chemical mixtures and estimated the combined risks of these to health. The study found that co-exposure to many substances of concern is very likely to occur in European adults and children, and that the possibility of subsequent health impacts from mixtures cannot be excluded. Six substances contributed to over 95% of the total risk: PFOS (perfluorooctancesulphonic acid), PFOA (perfluorooctanoic acid), arsenic, cadmium, di-n-butyl phthalate (DnBP) and di-iso-butyl phthalate (DiBP) (Socianu et al., 2022).

Another study investigated the association between combined exposure to chemical mixtures and deterioration in semen quality in a sample of Danish men. It found that tolerable exposures were exceeded by a large margin, with bisphenols, polychlorinated dioxins, phthalates and analgesics responsible for the health risk (Kortenkamp et al., 2022). Semen quality, in terms of both concentration and total count, is in general decline in Western countries (Levine et al., 2017).

A recent study explored changing phthalate exposure in the German population and the associated risks of exposure to mixtures over three decades. The decade from 1988 to about 1999 was characterised by potential risks to health from combined exposure to the chemicals di-n-butyl phthalate and DEHP (bis(2-ethylhexyl) phthalate). Notably, traditional single-substance risk assessments would have underestimated these risks by up to 50% compared with a combined assessment. Since 2006, assessment exposures based on a single phthalate have shown acceptable results — but combined exposures pose a risk to health (Apel et al., 2020). More recently, a Danish study explored combined exposure to phthalates among infants and their parents; it found that the threshold for effects on the endocrine system was exceeded in a number of both children and adults (Frederiksen et al., 2022). An assessment of the exposure of children and adolescents aged 6–18 years to phthalates from across 12 European countries was conducted under HBM4EU and found 17% of the children and adolescents to be at risk from combined exposure to five reprotoxic phthalates (Lange et al., 2022).


Towards zero pollution: assessing mixtures

While methodologies are available to assess mixtures (Bopp et al., 2019), they are not yet systematically applied across legislative sectors. A 2019 study from the Swedish government recommended clear legal requirements for mixture risk assessments in all relevant pieces of EU chemicals legislation (Rudén et al., 2019). The chemicals strategy for sustainability calls for the introduction of a mixture assessment factor in chemical safety assessments to address the combined effects of mixtures on human and environmental health.

New EU research projects such as the Horizon Europe Partnership for the Assessment of Risks From Chemicals (PARC) will tackle remaining knowledge gaps to support implementation of a mixture assessment factor across legislative sectors.



Apel, P., et al., 2020, ‘Time course of phthalate cumulative risks to male developmental health over a 27-year period: biomonitoring samples of the German Environmental Specimen Bank’, Environment International 137, 105467 (

Bopp, S. K., et al., 2019, ‘Regulatory assessment and risk management of chemical mixtures: challenges and ways forward’, Critical Reviews in Toxicology 49(2), pp. 174-189 (

Frederiksen, H., et al., 2022, ‘Exposure to 15 phthalates and two substitutes (DEHTP and DINCH) assessed in trios of infants and their parents as well as longitudinally in infants exclusively breastfed and after the introduction of a mixed diet’, Environment International 161, 107107 (

Kortenkamp, A., 2008, ‘Low dose mixture effects of endocrine disrupters: implications for risk assessment and epidemiology’, International Journal of Andrology 31(2), pp. 233-240 (

Kortenkamp, A., et al., 2022, ‘Combined exposures to bisphenols, polychlorinated dioxins, paracetamol, and phthalates as drivers of deteriorating semen quality’, Environment International 165, 107322 (

Lange, R., et al., 2022, ‘Cumulative risk assessment of five phthalates in European children and adolescents’, International Journal of Hygiene and Environmental Health, 246, pp.114052 (

Levine, H., et al., 2017, ‘Temporal trends in sperm count: a systematic review and meta-regression analysis’, Human Reproduction Update 23(6), pp. 646-659 (

Rudén, C., et al., 2019, Future chemical risk management: accounting for combination effects and assessing chemicals in groups. The report of the Committee of Combination of effects and assessing chemicals in groups, Swedish Government Official Reports ( accessed 21 October 2022.

Socianu, S., et al., 2022, ‘Chemical mixtures in the EU population: composition and potential risks’, International Journal of Environmental Research and Public Health 19(10), 6121 (

Cover image source: © Evangelija Ivanoska, Well with Nature /EEA


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